2 BEMAY THE KEY TO OUR MEMORIES MUCH-MALIGNEDHOW AMYLOIDS FUNCTIONAL AMYLOIDS STOWERS REPORT NEWS AND INSIGHT FROM THE STOWERS INSTITUTE FOR MEDICAL RESEARCH 2020 8 18 23 32 STOWERS REPORT PUBLISHED BY THE STOWERS INSTITUTE FOR MEDICAL RESEARCH 2020 DEPARTMENTS 2 FEATURES 18 THE EXCHANGE 18 A Discussion with Ron Conaway, PhD FUNCTIONAL AMYLOIDS: 20 IN A NUTSHELL A “MAGICAL” PROTEIN STATE Research roundup What’s old is new again How much-maligned amyloids 2 Technologies converge may be the key to our memories Survival of the fit-ish CRISPR knockdown Cavefish provide immunity insight Persistent DNA damage and pregnancy outcomes 23 24 SCIENTIFIC SCIONS Shuonan He: Finding evolutionary biology in the weird Predoc and postdoc awards and fellowships INSTITUTE NEWS 28 THE SPOTLIGHT WHEN SCIENCE MEETS ART Investigator honors and awards An intersection that creates beautiful results 32 8 32 ON CAMPUS Uncommon times require uncommon efforts Welte sails into retirement New leadership team hires Outreach and community engagement efforts expanded COVID-19 claims GSSIMR graduation ceremony Scientists in the making 36 SHARE OUR HOPE 36 Donor contributions 44 BACKSTAGE PASS Wednesday Lecture Series by the numbers NEW OSTEOPOROSIS ADVANCE ROOTED IN STOWERS RESEARCH CONTRIBUTORS: Visit the Stowers Institute at www.stowers.org or find us on Facebook at facebook.com/StowersInstitute Pioneering research helped lay the groundwork or Twitter @ScienceStowers. 15 Editors Scientific illustration for a new approach to treating the disease The Stowers Report is printed on recycled paper. Steve Bellis Mark Miller Kimberly Bland The Stowers Report is published by the Science Communications Department at the Stowers Institute Photography Kristin Kessler for Medical Research with support from the Stowers Foundation. We welcome your input. Please send Mark McDonald comments to [email protected] or contact us at (816) 926-4015. Copy editor Photography and illustration Bonny Moseley Philippe Noguera Web content Design and production Juan Carlos Grover Trozzolo Communications Group Brian Swezy FEATURES By Melissa Fryman Functional amyloids: A “magical” protein state How much-maligned amyloids may be the key to our memories Memory. For the majority of us, it is a constant companion, at times uninvited, and at others, cherished. Sometimes we strain to make and retain a fleeting memory, and at others, a memory seems nothing short of automatically installed, enduring a lifetime in our minds. It’s still mysterious, but the biological process that of Creutzfeldt-Jakob disease, which can arise from a underlies memory persistence is better understood genetic origin, or via transmission from an animal, as now than ever, thanks to researchers from the Si Lab in the human form of “mad cow” disease. at the Stowers Institute. Amyloids are protein aggregates with “In a general sense, memory is the ability of a characteristic structural features and have an system to experience something and then somehow equally bad reputation, being associated with such maintain a signature of that experience, even after the devastating neurodegenerative pathologies as experience has disappeared,” explains Investigator Alzheimer’s and Parkinson’s diseases, as well as and Associate Scientific Director Kausik Si, PhD. In Lewy body dementia. “The central hypothesis is that many biological entities, this capacity is centered in the protein misfolds and forms an amyloid—either the nervous system, and in particular at synapses, a smaller structure of repeating units or a larger which are the connection points between nerve cells. assembly that forms a fibril or fiber—and that it’s a Indeed, it was work done on the sensory-motor toxic entity,” says Si. neural circuit of the sea slug Aplysia californica, by Si 2 and Eric Kandel, MD, at Columbia University nearly 3 twenty years ago, that led to the initial surprising discovery about the molecular requirements for memory maintenance. Their discovery was twofold— an RNA-binding protein called CPEB (cytoplasmic polyadenylation element binding protein) is required for long-term synapse-specific modification, and in order to perform its full function in that capacity, CPEB has to self-assemble to form a functional protein aggregate that can self-renew, effectively acting like a prion. Prions are self-renewing protein aggregates, often amyloid aggregates, that have a deservedly frightful reputation. Perhaps the best-known prion in relation to human health is an infectious prion, the hallmark FEATURES Of their original finding in Aplysia, “that a protein in the A LONG HISTORY OF AMYLOID RESEARCH Together, the emergence of functional amyloids in yeast and bacteria nervous system can aggregate in a very specific situation The term “amyloid” first appeared in the scientific suggested the possibility that amyloids could be non-pathogenic. But nobody and can be a substrate of something that is stable literature in 1838, when it was used to describe the had ever thought that amyloids could be the substrate of memory. yet dynamic such as memory—that’s just completely amylaceous, or starch-like, makeup of plants that stained counter to what people were describing,” Si reflects. blue when exposed to iodine and sulphuric acid. It wasn’t “THEY THOUGHT I WAS OUT OF MY MIND” “Essentially the idea bumped into a hundred years of until 1854 that the term was popularized medically, by “When I thought about it and talked to some people, they thought I studies on protein aggregation and amyloids in the brain the “father of modern pathology” Rudolph Virchow, to was out of my mind. First of all, it’s a prion in the nervous system. that suggested one possibility—and then our finding describe small white deposits in the brain that stained Secondly, if it’s forming an amyloid in the nervous system, it cannot be suggested something radically different.” blue the same way starch did. doing anything good. Thirdly, people thought if amyloids are so stable, Over the years, Si and his team have built a strong “In some sense,” says Si, “from inception, amyloids were how can memory be reversible? After all, memory does change and case for amyloids as a substrate for memory. They associated with the wrong thing—the term was coined to seemingly disappear.” showed that CPEB proteins exist in the brains of mice and describe something that was supposed to be starch-like, but “I was trained as a physical chemist in India,” Si recounts. “I wanted to the fruit flyDrosophila melanogaster, where it is known now we know amyloids are made up of proteins.” switch fields and move to neuroscience, but nobody wanted to take me. So, as Orb2. Importantly, they found that as single units, Orb2 The molecular definition of amyloid emerged from the I actually went to a meeting where I talked to Eric, and I convinced him that binds to specific protein-encoding mRNA messages, work of biophysicist William Astbury, continues Si. “He saw he should let me join his group.” important for memory, located at synapses, acting to that denatured, or unfolded, albumin protein could form fibers “I was interested in a profound observation that Eric’s group had made. They When I thought repress protein production. As an amyloid assembly, by in a particular arrangement—layered zigzag-like structures had discovered if you stop protein synthesis in the synapse, the synapse can still about it and talked to contrast, Orb2 binds those mRNA messages at synapses called stacked b-sheets—with a standard distance between change but it cannot maintain that change over time.” and promotes production of those key synaptic proteins, the stacked layers forming the b-sheets of 4.7 angstroms.” “That finding suggested that the formation of memory and its some people, they leading to a persistent alternation in synaptic transmission A complementary definition of amyloid was derived subsequent maintenance have distinct requirements,” Si continues. To study thought I was out of that allows memory persistence. from the fact that plaques isolated from the brain could how memory sticks around, one must first understand how, and which Using memory assays, they be stained with Thioflavin T and Congo Red dyes. “In the proteins are made in the synapse. my mind. First of all, have shown not only that 1950s and ‘60s, Alan Cohen and colleagues connected “When I started out, I never thought it would lead me to prions and amyloids.” it’s a prion in the self-aggregated Orb2 the two. He isolated dye-stained material from the brain, is required for long- looked at it under an electron microscope, and found that “MAGICAL” PROTEIN STATE nervous system. term memory in some of the material had similar fibrous appearance.” That functional amyloids could exist in the nervous system “provided a very adult fruit flies Researchers then found that amyloid plaques isolated simple solution to one of the most complex biological processes,” says Si. Secondly, if it’s but also that from the brain were resistant to protein-destroying “Our findings suggested that a protein could be used like flipping a switch. forming an amyloid in already-formed enzymes and detergents. “This led to the idea that the By changing the conformation of a protein, the nervous system can encode memory is still amyloid state is an unintended consequence of proteins information on to a stable, yet changeable, physical substrate to achieve the nervous system, dependent being misfolded or unfolded, shortened, or otherwise something seemingly magical, such as memory.” it cannot be doing upon